The present invention relates to a new stable solid pharmaceutical formulation which is particularly suitable for the treatment of hypercholesterolemia and hyperlipidemia. More precisely, the present invention relates to the new stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cervastatin, or pharmaceutically active salts thereof.
Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and cervastatin, derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some are obtained by treating the fermentation products using the methods of chemical synthesis like simvastatin or they are the products of total chemical synthesis like fluvastatin, atorvastatin and cervastatin.
The purity of the active substance is an important factor for manufacturing a safe and effective pharmaceutical formulation. Maximum possible purity of the product is of particular importance if the pharmaceutical product must be taken on a longer term basis in the treatment or prevention of high cholesterol levels in blood. Accumulation of impurities from drugs of a lower level of purity may cause a variety of side effects during treatment. Besides impurities, that cannot be completely eliminated in the process of preparation of the active substance, degradation products occurring by subjecting the final pharmaceutical formulation to various environmental factors such as temperature, moisture, low pH and light, may also impose a problem. HMG-CoA reductase inhibitors occurring in the form of salts in the final pharmaceutical formulation, such as atorvastatin, pravastatin, fluvastatin and cervastatin, are particularly sensitive to an acidic environment in which hydroxy acids are degraded into a lactone.
Apart from the fact that the aforementioned active substance may be destabilised by the environmental factors, their degradation may also be accelerated by interactions with other pharmaceutical ingredients, such as fillers, binders, lubricants, glidants and disintegrating agents. Therefore, the pharmaceutical ingredients and the process for preparation of the pharmaceutical formulation should be meticulously chosen to avoid the aforementioned undesired interactions and reactions.
The stability of the active substance in an acidic environment is one of the major problems in the case of statins in the form of salts. One of possible solutions of the aforementioned problem is described in EP 0 336 298, disclosing a stable pharmaceutical formulation for pravastatin. The essence of the formulation is to maintain an alkaline environment so that the aqueous dispersion of the pharmaceutical formulation reaches a pH above 9, preferably about 10. In addition to the active substance pravastatin, the composition of the invention includes a basifying agent, such as magnesium oxide which imparts a pH to an aqueous dispersion of the aforementioned formulation above 9. In view of the stability of the active substance such a formulation is effective. However, the local alkaline environment occurring at the site of dissolution of the pharmaceutical formulation may have a negative impact on the gastric mucosa with its normally acidic environment. This negative impact may be particularly evident for patients with a damaged gastric mucous membrane where the mucosa per se is not able to create a sufficient acidic environment inside the stomach for normal digestive functioning. It is particularly important in chronic therapies as in the case of prophylaxis or treatment with HMG-CoA reductase inhibitors.
It is an object of the present invention to provide a pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor which exerts an excellent stability while avoiding the afore mentioned disadvantages. It is a particular object to provide a stabilized active substance as such where the HMG-CoA reductase inhibitor is precautionary protected from being degraded.
It is a further object to provide a process for the preparation of a stable pharmaceutical formulation which exerts an excellent stability while avoiding the afore mentioned disadvantages.
These and further objects are accomplished by the present invention.
According to the present invention, there is provided a stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, wherein an active substance is contained which is capable of providing a pH in the range from 7 to 11. Within the meaning of the present invention, the term xe2x80x9cactive substancexe2x80x9d denotes a HMG-CoA reductase inhibitor alone or a mixture thereof with a small amount of a buffering agent. Therefore, the present invention also makes available a stabilized pharmaceutically active substance as such, which active substance consists of a HMG-CoA reductase inhibitor and a low amount of a buffering agent.
According to the present invention, there is further provided a stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, wherein the pharmaceutical formulation is capable of providing a pH below 9.
In addition, according to the present invention, there is provided suitable processes for the preparation of the above specified stable solid pharmaceutical formulation.
According to the present invention, there is further provided a method for the stabilization of a HMG-CoA reductase inhibitor as an active substance in a solid pharmaceutical formulation, wherein an HMG-CoA reductase inhibitor being capable of providing a pH in the range from 7 to 11 is incorporated into a pharmaceutical formulation which is capable of providing a pH below 9.